1. Field of the Invention
The present invention relates to an agent for promoting either or both of the platelet and the leukocyte productions, more particularly, to an agent for promoting either or both of the platelet and the leukocyte productions in mammals including human, which contains as an effective ingredient interferon-.gamma. (hereinafter abbreviated as "IFN-.gamma.") and a biologically active substance(s) with either or both activities of promoting the platelet and the leukocyte productions (hereinafter abbreviated as "biologically active substance(s)", if not specified otherwise).
2. Description of the Prior Art
Platelets exist in mammalian blood, and, for example, human platelets are nuclear cells, 2-3 .mu.m in diameter, and exist in blood in a concentration of about 150,000-400,000 cells/mm.sup.3. Human platelets are released from matured megakaryocytes differentiated from pre-megakaryocytes after their proliferation and maturation. The life span of human platelets is about 11 days. Platelets successively contact with damaged endothelial cells in blood vessels, induce the adhesion and the aggregation reactions, and exert hemostasis.
Although the number of platelets in normal human blood is kept within the aforesaid range, it may be lowered by the reduction of platelet productivity in bone marrow, the platelet consumption, the promotion of platelet degradation in periphery, and the abnormal platelet distribution. The platelet reduction is caused, for example, by diseases which directly damage bone marrow such as osteomyelodysplasia, leukemia, cancer metastasis in bone marrow, myelomatosis, Hodgkin's disease, lymphosarcoma, myelofibrosis, myelosclerosis, hypertrophic osteoarthropathy, and osteopetrosis, and by other diseases which damage spleens such as Banti's syndrome, reticulum cell sarcoma, syphilis, and malignant tumors which induce splenomegaly. I. KIMURA and I. TAKAHASHI in "Toxicology Forum", Vol.11, No.2, pp.112-121 (1988) reported that the radio- and chemo-therapies used for treating malignant tumors damage bone marrow to cause platelet reduction.
Platelet reduction means a lowering of the function of hemostasis mechanism in vivo which causes skin petechial hemorrhage, rhinorrhagia, tunica mucosa oris hemorrhage, urinary tract hemorrhage, and genitalia hemorrhage, and it may sometimes causes alimentary canal bleeding and intracranial hemorrhage. Furthermore, the platelet reduction gives unfavorable effect on the treatment and the post-treatment of malignant tumors and diseases causative of the platelet reduction.
Blood component transfusion and self- and non-self-bone marrow transplantations are used to treat the platelet reduction. However, these treatments could not be a fundamental therapy for the platelet reduction because the transfusion has a demerit that the life span of platelets is shorter than that of other blood cells, and the transplantations have a demerit that the insertion of transplanted bone marrows is substantially difficult.
Recently, as reported by Ronald Hoffman in "Blood", Vol.74, No.4, pp.1,196-1,212 (1989), Erick M. Mazur in Experimental Hematology, Vol.15, pp.340-350 (1987), and Hava Avraham in "Stem Cells", Vol.11, pp.499-510 (1993), experiments in in vitro systems revealed that the differentiation and maturation of megakaryocytes, which correlate with the platelet level change, is influence by biologically active substances such as interleukin 3 (hereinafter abbreviated as "IL-3"), interleukin 6 (hereinafter abbreviated as "IL-6"), granulocyte colony-stimulating factor (hereinafter abbreviated as "G-CSF"), granulocyte/macrophage colony stimulating factor (hereinafter abbreviated as "GM-CSF"), stem cell growth factor (hereinafter abbreviated as "SCF"), thrombopoietin (hereinafter abbreviated as "TPO"), and erythropoietin (hereinafter abbreviated as "EPO").
Although many trails to increase the platelet productivity by administering biologically active substances to mammals to directly stimulate and grow megakaryocytes or to stimulate the differentiation induction, no satisfactory result is obtained because the growth and differentiation inducibilities of the used biologically active substances are relatively low and because the growth of megakaryocytes in vitro does not necessarily cause the platelet production in vivo.
As reported by Makio OGAWA in "Blood", Vol.81, No.11, pp.2,844-2,853 (1993), biologically active substances are generally known to have an activity of promoting the growth and the differentiation induction of megakaryocytes, and an activity of growing blood cell precursors, i.e. an activity of growing neutrophils, lymphocytes, erythrocytes, and mast cells in spleen. Therefore, these substances could not be specific to megakaryocytes: For example, Tadamitsu KISHIMOTO, in "Blood", Vol.74, No.1, pp.1-10 (1989) reported that IL-6 induces the maturation of blood cells in general, and L. Kanz et al. in "American Journal of Clinical Oncology", Vol.14, Supplement, pp.S27-S33 (1991), and Kazuo MOTOYOSHI in "Nippon Rinsho", Vol.50, No.8, pp.1,967-1972 (1992) reported that EPO induces the maturation of erythrocytes.
Recently, as reported by Frederic J. de. Sauvage et al. in "Nature", Vol.369, pp.533-538 (1994), Francoise Wendling et al. in "Nature", Vol.369, pp.571-574 (1994), See Rock et al. in "Nature", Vol.369, pp.565-568 (1994), and T. D. Bertley et at. in "Cell", Vol.77, pp.1,117-1,124 (1994), TPO as a biologically active substance was isolated, revealing that it has an activity of promoting the platelet production. However, the detailed mechanism still remains uncertain. Under these backgrounds, agents for promoting the platelet production, which effectively prevent and/or treat the platelet reduction in mammals including human without causing side effects, have been in great demand.
Leukocytes exist in vertebrate animals' blood and are produced by bone marrows. Normal human blood contains about 4,500-9,500 cells/mm.sup.3 of leukocytes which are classified roughly into phagocytes and immunocytes in hematology. Immunocytes include lymphocytes which have a major role of immunological function, while phagocytes include granulocytic cells and monocytic/macrophagic cells which have a phagocytic capacity to prevent vertebrate animals from bacteria, viruses and external substances. Although these Igbanulocytic cells and monocytic/macrophagic cells have a common phagocytic activity, the former first prevents bacteria and viruses, then the latter removes these microorganisms and eliminates the aged and denatured blood cells.
Although the number of leukocytes in normal human blood is kept within the aforesaid range, it may be lowered by the reduction of leukocyte productivity in bone marrow, the excessive exudation of leukocytes into inflammatory tissues and the following leukocytes' destruction, and the excessive consumption of leukocytes by infectious diseases. In addition, the leukocyte reduction is caused, for example, by diseases which directly damage bone marrow such as osteomyelodysplasia, aplastic anemia, leukemia, cancer metastasis in bone marrow, myelomatosis, Hodgkin's disease, lymphosarcoma, myelosclerosis, hypertrophic osteoarthropathy, and osteopetrosis, and other diseases which damage spleens and livers such as Banti's syndrome, reticulum cell sarcoma, syphilis and malignant tumors with splenomegaly.
Leukocyte reduction means a lowering of the function of hemostasis mechanism in vivo and gives unfavorable influence on the treatment and the post-treatment of malignant tumors and diseases causative of leukocytopenia.
Self- and non-self-bone marrow transplantations are used to treat the leukocyte reduction. However, such treatments could not be the fundamental therapy for leukocyte reduction because the insertion of the transplanted bone marrows is substantially difficult.
Recently, as reported by Sucha Nand et al., in "Blood", Vol.83, No.2, pp.357-360 (1994), A. Ganser et al., in Leukemia, Vol.7, No.5, pp.696-701 (1993), and Razelle Kurzrock et al., in Journal of Clinical Oncology", Vol.9, No.7, pp.1,241-1,250 (1991), it was revealed that biologically active substances such as interleukin 3 (hereinafter abbreviated as "IL-3") and granulocyte/macrophage colony stimulating factor (hereinafter abbreviated as "GM-CSF") have an activity of promoting the leukocyte production, and their phase I and phase II clinical trials have been conducted. However, these trials have problems that these biologically active substances could not be administered to some patients because they should be administered to the patients in a relatively large amount of which causes side effects.
Although a variety of medicaments except for the aforesaid biologically active substances have been used as an agent for leukopenia, no satisfactory result has been obtained. Under these backgrounds, agents for promoting the platelet and the leukocyte productions, which effectively prevent and/or treat the symptoms without causing side effects, have been in great demand.